Severe Pneumonia Caused by Coinfection With Influenza Virus Followed by Methicillin-Resistant Staphylococcus aureus Induces Higher Mortality in Mice

Abstract

Background: Coinfection with influenza virus and bacteria is a major cause of high mortality during flu pandemics. Understanding the mechanisms behind such coinfections is of utmost importance both for the clinical treatment of influenza and the prevention and control of epidemics.Methods: To investigate the cause of high mortality during flu pandemics, we performed coinfection experiments with H1N1 influenza virus and Staphylococcus aureus in which mice were infected with bacteria at time points ranging from 0 to 7 days after infection with influenza virus.Results: The mortality rates of mice infected with bacteria were highest 0–3 days after infection with influenza virus; lung tissues extracted from these co-infected mice showed higher infiltrating cells and thicker lung parenchyma than lung samples from coinfected mice in which influenza virus was introduced at other times and sequences. The levels of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-8, and IL-6 in the 0–3 day coinfected group were significantly higher than those in the other groups (p < 0.01), as were the mRNA levels of IFN-γ, IL-6, and TNF-α. Coinfection with influenza virus and S. aureus led to high mortality rates that are directly dependent on the sequence and timing of infection by both pathogens. Moreover, coinfection following this particular schedule induced severe pneumonia, leading to increased mortality.Conclusions: Our data suggest that prevention of bacterial co-infection in the early stage of influenza virus infection is critical to reducing the risk of clinical mortality.

Evaluation of bacterial co-infections of the respiratory tract in COVID-19 patients admitted to ICU

“…Randolph et al also reported that among 838 children with influenza A (H1N1) virus admitted to a pediatric intensive care unit during the 2009 influenza A (H1N1) pandemic, 71 (8.5%) had a presumed diagnosis of early S. aureus co-infection of the lung with 48% positive for MRSA [46]. Moreover, Jia et al project on mouse model findings also showed that secondary infection with methicillin-resistant Staphylococcus aureus after infection with influenza virus was associated with high mortality rates [47]. Another study by Liu et al also confirmed that the co-infection of avian influenza A (H7N9) virus and extensively antibiotic-resistant A. baumannii in the patients with invasive mechanical ventilation is a key factor for the severity of the disease and high mortality [48].…”

IL-6 During Influenza-Streptococcus pneumoniae Co-Infected Pneumonia—A Protector

“…Previous reports have shown that IL-6 was detected in the lungs and circulation of patients from the 1918 and 2009 H1N1 influenza pandemics (1,(23)(24)(25). IL-6 as the most upregulated cytokine upon IAV-S. pneumoniae co-infected mice have been revealed in recent researches (8,9).…”

Dysregulated Host Responses Underlie 2009 Pandemic Influenza-Methicillin Resistant Staphylococcus aureus Coinfection Pathogenesis at the Alveolar-Capillary Barrier

“…IL-6 levels have been shown to be significantly elevated in the presence of a clinically relevant secondary bacterial infection, which may make its upregulation in pH1N1-MRSA coinfection unsurprising [ 54 , 74 ]. It is enticing to speculate that IL-6 upregulation may be related to increased barrier permeability found in our pH1N1-MRSA ECIS results, as high levels of IL-6 are known to directly damage endothelial cells [ 75 ]. Further, elevated serum IL-6 levels have been implicated as a potential biomarker for disease severity in pH1N1-alone infections [ 76 ].…”